The overall purpose of the proposed studies is to elucidate the role of the female reproductive hormones relaxin, estrogen and progesterone in the etiopathogenesis of temporomandibular joint (TMJ) disease in women. Despite the debilitating nature of temporomandibular disorders (TMDs) and a gender predilection as high as 10:1 in women mainly in their reproductive age, the etiology and pathogenesis of these disorders remain unknown. Although a role for female reproductive hormones, particularly estrogen, has been proposed, little evidence in support of this theory has been presented. Additionally, the potential role of other female reproductive hormones such as relaxin in TMDs has not been examined. We have recently demonstrated that relaxin induces a matrix- degradative phenotype in cultured TMJ disc cells by increasing the expression of the matrix metalloproteinases collagenase and stromelysin. Priming of the cells with beta-estradiol produces a 10-fold increase in their responsiveness to relaxin. Furthermore, our preliminary studies of women with or without symptoms of TMJ disorders reveal that women with the most severe manifestations of TMJ disease have the highest serum levels of relaxin and beta-estradiol as compared to controls or women with less severe manifestations of the disease. Additionally, both the proportion of women reporting previous pregnancies (44% versus 10.5%) and the mean number of pregnancies (0.8 versus 0.1) were significantly greater (P less than or equal to 0.02) in symptomatic than in asymptomatic women. Although these studies suggest that relaxin together with beta-estradiol may cause or predispose to TMJ disease, further evidence is needed to establish a definitive link between these hormones and TMJ disease. Therefore, using a case control study design on symptomatic and asymptomatic women and a longitudinal prospective study design on pregnant women, we will test the hypothesis that perturbations in the absolute levels or the relative balance of relaxin,beta-estradiol and progesterone predispose to TMJ disease in women of reproductive age. In order to provide a basis for a non-invasive, more efficient and less expensive alterative to relaxin assays on serum, we will also determine whether relaxin levels in saliva correlate with those in serum. Together, our human and basic sciences investigations may help to identify the potential hormonal etiology of TMJ disease, and may be critical in designing specific diagnostic assays and biologically rational therapies for these diseases in women.